An increasing number of familial cases suggest that MRKH syndrome can be inherited as an autosomal dominant incompletely penetrant trait, either due to single gene mutation or chromosomal imbalances [
1]. Clinical features are consistent with a developmental defect attributable to an initial affection of the intermediate mesoderm leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts [
6], but developmental genes investigated, such as
WT1,
HOXA7,
HOXA13 and
PBX1, did not reveal any pathogenic mutation [
7,
8]. Among chromosome causes, an identical t(12;14)(q14;q31) detected in two unrelated Indian females, a maternally inherited terminal deletion of 4q and 22q11.21 deletion, overlapping the DiGeorge syndrome region, have been described in females with syndromic MRKH. However, so far no candidate gene was identified in the unbalanced regions [
9‐
11].
Array-CGH technique has offered in the last years new opportunities to discover cryptic chromosome imbalances causative of congenital malformations. This approach allowed Cheroki et al. to confirm the involvement of 22q region in the MRKH aetiology [
12] and to detect a
de novo deletion at 17q12 in one patient presenting with absent uterus, severe learning disability and seizures, without diabetes and renal malformations [
13]. We have reported two patients evaluated for Müllerian ducts aplasia in which array-CGH analysis disclosed an identical deletion at chromosome 17q12, spanning about 1.5 Mb of genomic DNA. One patient displayed congenital absence of uterus and vagina, with bilaterally normal ovaries without any additional anomaly, while the other had agenesis of the upper part of vagina, right unicornuate uterus and non cavitating rudimentary left horn associated with bilaterally multicystic kidneys. In both patients psychomotor development was normal. This is a rare albeit recurrent imbalance detected so far in a few other subjects investigated using genomic microarray. Mefford et al. identified the same 1.5 Mb deletion in a foetus presenting with grossly abnormal, dysplastic multicystic kidneys and compared this case with five paediatric patients with renal disease and three subjects affected by isolated MODY5. It was found that the breakpoints were identical in all but one case, who displayed a larger deletion, and occurred at segmental-duplication clusters with multiple regions of high identity (up to 99%) [
14]. The deleted segment encompassed 16 known genes, including
TCF2 and
LHX1. Mutations in
TCF2 gene, also known as hepatocyte nuclear factor-1-beta (
HNF1β), which occur in individuals affected by maturity-onset diabetes of the young type 5 (MODY5; MIM 137920) and renal manifestations [
15], have been associated with Müllerian disorders [
1]. In particular, two of four affected females in a MODY5 family segregating
TCF2 mutations had Müllerian aplasia [
16], while in another MODY5 family, the proband displayed cystic kidneys and uterus didelphys and her affected second son had renal cysts and hypospadias [
17].
TCF2 is expressed in renal metanephroi at preglomerular stages during metanephrogenesis [
18]. Urinary and genital system are embryologically correlated, both originating from a common mesodermal ridge. Edghill et al. [
19] have estimated that about 10% of subjects with
TCF2 mutations also display some genital system anomaly.
LHX1 encodes a transcription factor with a DNA-binding homeodomain and two cysteine-rich LIM domains that are thought to be involved in protein-protein interactions [
20]. In mouse, this gene was shown to be involved in genitourinary system developmental processes, including Müllerian ducts [
21]. To assess the contribution of these genes to MRKH syndrome, we performed a mutational analysis of 20 non deleted MRKH females. Analysis of 40 chromosomes disclosed several polymorphic changes, in the absence of any pathogenic variation.